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Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen”

The following article, Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen”, was first published on 100PercentFedUp.com.

Is Joe Biden going to become the Democrat nominee and run against Trump in the fall?

Continue reading: Rush Limbaugh Predicts Joe Biden Won’t Be The Dem Nominee: “Something’s Gonna Happen” ...




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Windsor Assembly Plant on track for May 19 restart

The Fiat-Chrysler Windsor Assembly Plant looks to be on track for a May 19 reopening according to union leadership.




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Traffic stop in Windsor leads to multiple charges and discovery of homemade conducted energy weapon

After being pulled over for what started as a traffic violation, two Windsor men were arrested and face multiple drug, property, and weapon related charges.




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Owners of new retail cannabis store hoping to open soon in Pillette Village

At a time when store front vacancies are growing thanks to COVID-19, a new retail cannabis store in Pillette Village is hoping to open soon.




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OPP release composite drawing of man who allegedly impersonated an officer

Essex County OPP have released a composite drawing of a suspect reported to be impersonating a police officer in Lakeshore.




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One new death and nine new COVID-19 cases in Windsor-Essex

One more person has died from the coronavirus in the Windsor-Essex region on Saturday and nine new cases have been reported by the health unit.




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Overnight snow expected in areas of Southern Manitoba

Environment Canada has issued a special weather statement for the southwestern area of Manitoba.




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May snowstorm buries southwest Manitobans

Instead of May flowers, Manitobans in the southwest part of the province received a blanketing of snow for Mother's Day weekend.




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A peroxisome deficiency-induced reductive cytosol state up-regulates the brain-derived neurotrophic factor pathway [Metabolism]

The peroxisome is a subcellular organelle that functions in essential metabolic pathways, including biosynthesis of plasmalogens, fatty acid β-oxidation of very-long-chain fatty acids, and degradation of hydrogen peroxide. Peroxisome biogenesis disorders (PBDs) manifest as severe dysfunction in multiple organs, including the central nervous system (CNS), but the pathogenic mechanisms in PBDs are largely unknown. Because CNS integrity is coordinately established and maintained by neural cell interactions, we here investigated whether cell-cell communication is impaired and responsible for the neurological defects associated with PBDs. Results from a noncontact co-culture system consisting of primary hippocampal neurons with glial cells revealed that a peroxisome-deficient astrocytic cell line secretes increased levels of brain-derived neurotrophic factor (BDNF), resulting in axonal branching of the neurons. Of note, the BDNF expression in astrocytes was not affected by defects in plasmalogen biosynthesis and peroxisomal fatty acid β-oxidation in the astrocytes. Instead, we found that cytosolic reductive states caused by a mislocalized catalase in the peroxisome-deficient cells induce the elevation in BDNF secretion. Our results suggest that peroxisome deficiency dysregulates neuronal axogenesis by causing a cytosolic reductive state in astrocytes. We conclude that astrocytic peroxisomes regulate BDNF expression and thereby support neuronal integrity and function.




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N{alpha}-Acetylation of the virulence factor EsxA is required for mycobacterial cytosolic translocation and virulence [Molecular Bases of Disease]

The Mycobacterium tuberculosis virulence factor EsxA and its chaperone EsxB are secreted as a heterodimer (EsxA:B) and are crucial for mycobacterial escape from phagosomes and cytosolic translocation. Current findings support the idea that for EsxA to interact with host membranes, EsxA must dissociate from EsxB at low pH. However, the molecular mechanism by which the EsxA:B heterodimer separates is not clear. In the present study, using liposome-leakage and cytotoxicity assays, LC-MS/MS–based proteomics, and CCF-4 FRET analysis, we obtained evidence that the Nα-acetylation of the Thr-2 residue on EsxA, a post-translational modification that is present in mycobacteria but absent in Escherichia coli, is required for the EsxA:B separation. Substitutions at Thr-2 that precluded Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the host membrane, resulting in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamics simulations revealed that at low pH, the Nα-acetylated Thr-2 makes direct and frequent “bind-and-release” contacts with EsxB, which generates a force that pulls EsxB away from EsxA. In summary, our findings provide evidence that the Nα-acetylation at Thr-2 of EsxA facilitates dissociation of the EsxA:B heterodimer required for EsxA membrane permeabilization and mycobacterial cytosolic translocation and virulence.




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ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells [Molecular Bases of Disease]

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.




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Prominins control ciliary length throughout the animal kingdom: New lessons from human prominin-1 and zebrafish prominin-3 [Cell Biology]

Prominins (proms) are transmembrane glycoproteins conserved throughout the animal kingdom. They are associated with plasma membrane protrusions, such as primary cilia, as well as extracellular vesicles derived thereof. Primary cilia host numerous signaling pathways affected in diseases known as ciliopathies. Human PROM1 (CD133) is detected in both somatic and cancer stem cells and is also expressed in terminally differentiated epithelial and photoreceptor cells. Genetic mutations in the PROM1 gene result in retinal degeneration by impairing the proper formation of the outer segment of photoreceptors, a modified cilium. Here, we investigated the impact of proms on two distinct examples of ciliogenesis. First, we demonstrate that the overexpression of a dominant-negative mutant variant of human PROM1 (i.e. mutation Y819F/Y828F) significantly decreases ciliary length in Madin–Darby canine kidney cells. These results contrast strongly to the previously observed enhancing effect of WT PROM1 on ciliary length. Mechanistically, the mutation impeded the interaction of PROM1 with ADP-ribosylation factor–like protein 13B, a key regulator of ciliary length. Second, we observed that in vivo knockdown of prom3 in zebrafish alters the number and length of monocilia in the Kupffer's vesicle, resulting in molecular and anatomical defects in the left-right asymmetry. These distinct loss-of-function approaches in two biological systems reveal that prom proteins are critical for the integrity and function of cilia. Our data provide new insights into ciliogenesis and might be of particular interest for investigations of the etiologies of ciliopathies.




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A neuroglobin-based high-affinity ligand trap reverses carbon monoxide-induced mitochondrial poisoning [Molecular Biophysics]

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ± 19% reduction in tissue respiration rate and a 33 ± 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC–treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 μm) and nitric oxide (100 μm). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 μm, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.




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Five Lessons From the New Arab Uprisings

12 November 2019

Dr Georges Fahmi

Associate Fellow, Middle East and North Africa Programme
Georges Fahmi examines how protesters across the region have adapted their tactics after the experiences of the Arab Spring.

The second wave of Arab uprisings that started in Sudan in December last year and extended to Algeria, Lebanon and Iraq this year have built on past experiences of political transitions during the Arab Spring, both its mistakes and achievements. Protesters from this new wave have already learned five lessons from previous transitions.

The first lesson is that toppling the head of a regime does not mean that the political regime has fallen.  In Tahrir Square on 11 February 2011, Egyptian protesters celebrated the decision of Hosni Mubarak to step down and left the square, thinking his resignation was enough to allow a democratic transition to take place. In contrast, in Sudan and Algeria, protesters continued to demonstrate after the resignation of Abdelaziz Bouteflika and the military-led ousting of Omar al-Bashir.

Protesters understood the lesson that the regime is found not only in the head of the state, but rather in the rules that govern the political sphere. By extension, political change requires changing the rules, not just the names of those in charge of implementing them.

The second lesson is that resorting to violence is the fastest way to end any hope for democratic change. Protesters who decided to take up arms offered their regimes the chance to reframe the political uprisings as civil war, as was the case in Syria. Even when armed groups manage to bring down the regime, their presence endangers the transitional phase afterwards, as is the case in Libya.

Although protesters in Sudan and Iraq have been faced with government violence and repression, they have insisted on their non-violent approach. In Sudan, the protesters responded to the massacre outside of the General Command of the Armed Forces on 3 June by organizing a mass demonstration on 30 June, which put pressure on the military to resume talks with the revolutionary forces.

The third lesson is that once the old regime has fallen, the transition period must be a collective decision-making process in which the opposition has, at least, veto power. The example of Tunisia after 2011 is a case in point. The Higher Authority for Realization of the Goals of the Revolution, Political Reform and Democratic Transition, which formulated the planned course of the transition, included representatives from across the political spectrum and civil society.

Although the military forces in Algeria and Sudan will not cease to play a political role any time soon, this does not have to mean exerting complete control over the transitional period. Sudan could offer a positive example in this regard, if it succeeds in implementing a power-sharing deal according to which a joint civilian-military sovereign council will govern Sudan during the transitional period.

The fourth lesson is that political transitions should achieve agreement on the rules of the game before proceeding to elections. In Egypt after 2011, rushed elections served to divide the political opposition and dramatically increase polarization in society. In this second wave, protesters have perceived elections as a trap which enable old regimes to reproduce themselves with new names.

In both Algeria and Sudan, protesters have resisted attempts by the military to hold elections as soon as possible. In Sudan, the agreement between the revolutionary forces and the military council postponed the elections until after the end of a three-year transitional period of technocratic rule. In Algeria, protesters are taking to the streets every Friday to demonstrate against the authorities’ decision to hold presidential elections in December.

The fifth and final lesson is that the call for change in the region goes beyond electoral democracy and extends to deep socioeconomic reforms. Iraq and Lebanon show this clearly: relatively free and fair elections have already been held but have served only to reinforce corrupt sectarian regimes.

According to the fifth wave of the Arab Barometer, the economic situation and corruption are perceived as the main challenge for Algerians (62.2%), Sudanese (67.8%), Lebanese (57.9%), and Iraqis (50.2%), while democracy is perceived as the main challenge for only 2.3%, 3.9%, 5% and 1.4% respectively.  The experience of the Arab Spring has shown people that democratic measures are only a means to an end.

Unlike in 2011, when the Arab Spring revolts enjoyed broad international support, this second wave is taking place in a hostile environment, with stronger Russian and Iranian presences in the region and an indifferent international climate. But where protesters have the advantage is in experience, and across the region they are clearly adapting their tactics to lessons learned from the early part of the decade.




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How the Soleimani Assassination Will Reverberate Throughout the Middle East

6 January 2020

Dr Sanam Vakil

Deputy Director and Senior Research Fellow, Middle East and North Africa Programme

Dr Renad Mansour

Senior Research Fellow, Middle East and North Africa Programme; Project Director, Iraq Initiative

Dr Lina Khatib

Director, Middle East and North Africa Programme
Regional experts examine how Iran benefits from the fallout of the killing, the implications for politics in Iraq and how Tehran might respond with its proxies in the region.

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Protesters hold up an image of Qassem Soleimani during a demonstration in Tehran on 3 January. Photo: Getty Images.

An unexpected bounty for Iran

Sanam Vakil

The assassination of Qassem Soleimani has been an unexpected bounty for the Islamic Republic at a time when Iran was balancing multiple economic, domestic and regional pressures stemming from the Trump administration’s maximum pressure campaign.

Coming on the heels of anti-Iranian demonstrations in Iraq and Lebanon, and following Iran’s own November 2019 protests that resulted in a brutal government crackdown against its own people, the Soleimani killing has helped the Iranian government shift the narrative away from its perceived regional and domestic weaknesses to one of strength.  

The massive funeral scenes in multiple Iranian cities displaying unending waves of mourners chanting against the United States has provided the Islamic Republic with a unique opportunity to showcase its mobilizing potential. This potential is not limited to Iran but also extends to Iraq and Lebanon, where Tehran’s transnational summoning power has also been visible. The Iraqi parliamentary vote to end the American military presence is one early negative consequence. While the region awaits Iran’s response, further anti-American rallying cries will continue to reverberate.  

Domestically, Soleimani’s death and President Donald Trump’s continued provocations on Twitter, including threats to attack 52 Iranian cultural sites, are being used as a nationalist rallying cry. This sentiment should not be seen solely as Islamic or ideological, but rather an opportunity for the state to pivot to an Iranian-based nationalism that is more inclusive and empowering for much of the country’s disgruntled youth.

Iran’s notoriously divided political factions have also unified in the face of this crisis. With parliamentary elections looming in February and turnout previously expected to be low, the political establishment is likely to use this crisis to mobilize voters in favour of conservative candidates.  

How Tehran chooses to respond to Qassem Soleimani’s death will very much determine its ability to continue to control the narrative and manage its swell of domestic and regional support. For these benefits to continue to manifest, it is important for Tehran to balance the mix of public sympathy and international anxiety and not overplay its hand in its quest for revenge.

A reset for Iraqi politics

Renad Mansour

The US strike which killed Qassem Soleimani and Abu Mehdi al-Muhandis has grave implications for Iraq. The act jeopardizes Iraq’s recently stabilized security situation, and threatens to reshape the country’s political environment, moving backwards to the days of anti-Americanism and sect-based mobilization. If Baghdad loses relations with the US and other diplomatic representations, it risks turning into a pariah state. 

Over the past few years, and notably since October 2019, young Iraqis have taken to the streets demanding reform and the downfall of the political establishment, and its main external backer Iran. The political establishment, including political parties and militias close to Tehran, failed to appease or suppress these protests. Now, these political elites are using the deaths of Muhandis and Soleimani to (re)gain popularity from their own population, by drawing on the old tool of anti-Americanism. 

Following the attacks, Shia populist cleric Muqtada al-Sadr – who until recently had called for an end to Iranian and pro-Iranian militia influence in Iraq – has called to revamp the Mehdi Army that he led until 2008 and is calling for ‘Islamic resistance’ to the US. In seeking to regain control of his former movement, he is coming closer to former Shia foes.

For years, pro-Iranian groups attempted to push the US out of Iraq. Their calls often fell on deaf ears, as public opinion in Iraq did not consider the US as a threat and some even supported the US and international effort against ISIS. Following the attacks, however, anti-American voices have gained more ammunition.

A complete American withdrawal would not only have direct security implications but force other countries and organizations, from European states to NATO, to reconsider their positions and role.

Limited options for ‘revenge’ in the Levant

Lina Khatib

Iran’s use of Lebanon and Syria as spaces for revenge against the US is unlikely.

On Sunday, Hezbollah leader Hassan Nasrallah vowed revenge for Soleimani’s death by singling out American soldiers as a target. However, Hezbollah’s options are limited. Lebanon is in the middle of wide-ranging protests against the country’s ruling political class, of which Nasrallah is a key figure.

Unlike in 2006, when Hezbollah’s military actions against Israel rallied the public around it, today there is no public appetite for dragging Lebanon into a war. Were Hezbollah to instigate one, it would incur public anger, if only for the economic repercussions that would exacerbate an already severe financial crisis in Lebanon. Lebanon also does not have any US military bases that could be a target for Hezbollah.

In theory, Hezbollah or other Iranian-backed groups could attack American bases in Syria. But these bases are staffed by multinational forces from the international anti-ISIS coalition. Attacking them would therefore put Iran in confrontation with other countries besides the US, which is not in Iran’s interest.

Attacking US soldiers in northeast Syria would also go against Kurdish interests because it would weaken the anti-ISIS coalition front of which Kurdish forces are part. It would, furthermore, anger Arab tribes in the area, opening up possibilities for ISIS to take advantage of public dissent to stage a comeback. Iran would then find itself fighting on several fronts at once, which it does not have the capacity to handle. 

More likely, Iran’s allies and proxies in the Levant are going to engage in strong rhetoric without taking hasty actions. When a key Hezbollah leader, Imad Mughniyeh, was assassinated in Damascus on 2008, there were strong words and public vows to seek revenge for his killing, but ultimately there was no response.    




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COVID-19 Impact on Refugees is Also Political

31 March 2020

Dr Lina Khatib

Director, Middle East and North Africa Programme
The spread of coronavirus in the Levant puts Syrian as well as other refugees and internally displaced people at particular risk because of the policies and practices of the authorities.

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The word Corona written in the sand on the beach in Lebanon's southern city of Saida. amid the spread of coronavirus in the country. Photo by MAHMOUD ZAYYAT/AFP via Getty Images.

As Lebanon strains to contain COVID-19, it is not clear which governmental public health policies apply to refugees. The government announced free testing for coronavirus in the public Rafiq Hariri University Hospital in Beirut but has not mentioned if refugees are eligible.

Lebanon’s coronavirus containment strategy is based on self-reporting and, given incidents of forced deportation and harassment of Syrian refugees from both the authorities and local communities, it is certainly less likely refugees would present themselves to the health authorities for fear of deportation.

Despite agreeing a Lebanon Crisis Response Plan with the UN for refugees, different ministries were left to implement it without coordination, just as Lebanese politicians from all sides started trying to rally popular support for ridding Lebanon from refugees - in particular from Syria, who Lebanese leaders say are causing a strain on the country’s already weak infrastructure.

This finger pointing is coupled with the leaders’ own complete disregard for the rampant corruption and lack of accountability within Lebanon’s political class, which contribute to the weakening of the country’s infrastructure.

For refugees who do find themselves back in Syria, there are different challenges according to which area they are in. In the north-east, the WHO and international NGOs (INGOs) negotiate with both Kurdish authorities as well as the government - each presenting its own hurdles.

Kurdish authorities in northeast Syria have closed the Semalka border with Iraqi Kurdistan, posing a serious dilemma for INGOs offering services in north-east Syria but concerned about their staff safety whose movement is now curtailed.

The government of Syria has stipulated all emergency response must go through its ministries. But this limits what the WHO can do in the country and gives Syrian authorities the ability to block ‘cross-line aid’ which goes from government-controlled to non-government areas.

Despite reports that doctors raised the alarm about suspected cases well before patient zero was confirmed, the government appears to be either covering up the actual extent of the spread of COVID-19 or failing to respond. Some limited testing kits have arrived but testing has barely started.

The WHO’s Syria plan is divided into three regions (north-west, north-east, and areas under government control). But concerns remain as to how workable such a decentralized plan is because of the government’s practices. In January, the UN Security Council did not renew the cross-border response resolution for the Yaroubiye border crossing between Syria and Iraq that the WHO was using to send medical supplies into north-east Syria.

Syrian authorities do not permit recently authorized ‘cross-line’ responders to engage with non-government authorities in areas outside regime control. This essentially voids the authorization to work cross-line as it is practically impossible to implement programs. The WHO has sought approval from the Syrian Ministry of Foreign Affairs to move medical supplies by land to north-east Syria.

While promising facilitation, the Ministry’s reply comes with conditions of seeking detailed approval for every shipment. When Eastern Ghouta was under siege, similar conditions led to certain supplies being removed from UN/ICRC convoys to Eastern Ghouta, and there is no guarantee this will not happen again.

Due to lack of capacity in north-east Syria, coronavirus tests conducted by the WHO there must be processed through the Central Public Health Laboratory in Damascus. Samples are transported twice a week from Qamishli to Damascus but no results were ever received from Damascus for those tests.

While the WHO is able to coordinate access to north-west Syria with the Turkish authorities, the prospective coronavirus testing capacity in the Idlib region is low – despite claims that thousands of kits are arriving, a lack of resource on the ground means potentially only 20 tests per day could be done in an area inhabited by an estimated three million people.

Following the recently announced ceasefire in the area, many internally displaced people are returning from the Turkish border to their homes in the north-west, but such mass movement increases the risk of coronavirus spreading. People also continue to move between Syria, Iraq, Turkey and Lebanon, posing a challenge to the WHO’s COVID-19 response in the Levant, as the WHO has distinct response plans for each country in the region and it is difficult to coordinate across these plans.

Challenges face refugees even if they head towards Europe due to the potential for conflation between migration control and coronavirus outbreak control. Aurelie Ponthieu, Coordinator for Forced Migration at Médecins Sans Frontières (MSF) says there is a risk some countries could use COVID-19 to impose draconian measures towards asylum seekers.

The crisis has also put a halt to search and rescue operations in the Mediterranean because European countries are not allowing boats carrying migrants to disembark under the pretext of limiting the spread of coronavirus. And for migrants who already made it - such as in Greece - they are now being put in collective quarantines in asylum centers, often with poor medical facilities.

Ponthieu also reports that migrants being quarantined on overcrowded navy ships docked in Greek ports, making social distancing impossible. And she is concerned the Greek authorities are imposing a curfew on asylum seekers but not on the local population.

UNHCR is stressing that people’s right of asylum must not be overruled by concerns about the spread of coronavirus, while local and international NGOs across the Levant are trying to coordinate their advocacy on lifting restrictions on freedom of movement for humanitarian workers and on other policies and practices by authorities in the region which are adversely affecting refugee and other vulnerable communities.

The international community must not lose sight of the impact of the crisis on refugees and migrants. It is not enough simply to supply humanitarian and medical assistance without paying attention to the policies and practices of the different authorities who have direct control over the fate of vulnerable communities.

The author would like to thank Aurelie Ponthieu and the two INGO field workers who all agreed to be interviewed to inform this analysis piece.




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Webinar: Can the Justice and Development Party Still Absorb Popular Anger in Morocco?

Webinar Research Event

8 April 2020 - 1:00pm to 2:00pm

Event participants

Mohammed Masbah, Director, Moroccan Institute for Policy Analysis; Associate Fellow, MENA Programme, Chatham House
Moderator: Lina Khatib, Director, MENA Programme, Chatham House

Ever since independence, the Moroccan monarchy has used political parties to legitimize the country’s authoritarian political process and structure, and to absorb social and political anger. The palace puts successive governments and other elected institutions, such as local and regional councils, at the frontline of public blame, and replaces them once they fail this function.

In a recent article, MENA Programme Associate Fellow, Mohammed Masbah, examines how the Moroccan monarchy has used this strategy with the ruling Justice and Development Party (PJD) so that the palace remains the centre of political power, while the PJD – and other political parties before it– takes responsibility for coping with the mounting socio-economic crisis.

In this webinar, part of the Chatham House project on The Future of the State in the Middle East and North Africa, the article’s author will discuss the risks this approach presents for the long-term stability of Morocco and what reforms are needed to increase citizens’ dwindling confidence in the political process.

You can express your interest in attending by following this link. You will receive a Zoom confirmation email should your registration be successful.




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Webinar: Are the Gulf Standoffs Resolvable?

Research Event

21 April 2020 - 1:00pm to 2:00pm

Event participants

David Roberts, Assistant Professor and School of Security Studies Lead for Regional Security and Development, King's College London
Kristian Coates Ulrichsen, Associate Fellow, Middle East and North Africa Programme, Chatham House
Chair: Sanam Vakil, Deputy Director and Senior Research Fellow, Middle East and North Africa Programme, Chatham House

This webinar, part of the MENA Programme Webinar Series, will examine the trajectory of political and security dynamics in the Gulf in view of the ongoing rift within the Gulf Cooperation Council (GCC), the death of Sultan Qaboos in Oman, the escalation of tensions between Iran and the United States, and the COVID-19 crisis.

Speakers will explore the orientation of the GCC under a new Secretary-General and the prospects for mediation between Qatar and its neighbours, the future of Omani domestic and foreign policy under Sultan Haitham bin Tariq Al Said, eventual transitions to new leadership in Bahrain and Kuwait, and whether the impact of COVID-19 may help replace the confrontation within the GCC with closer coordination among its six member states.

The webinar will be livestreamed on the MENA Programme Facebook page.

Reni Zhelyazkova

Programme Coordinator, Middle East and North Africa Programme
+44 (0)20 7314 3624




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Same Old Politics Will Not Solve Iraq Water Crisis

15 April 2020

Georgia Cooke

Project Manager, Middle East and North Africa Programme

Dr Renad Mansour

Senior Research Fellow, Middle East and North Africa Programme; Project Director, Iraq Initiative

Glada Lahn

Senior Research Fellow, Energy, Environment and Resources Programme
Addressing Iraq’s water crisis should be a priority for any incoming prime minister as it is damaging the country’s attempts to rebuild. But successive governments have allowed the problem to fester.

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Punting in the marshes south of the Iraqi city of Ammarah. Photo by Ghaith Abdul-Ahad/Getty Images.

Historically, Iraq lay claim to one of the most abundant water supplies in the Middle East. But the flow of the Tigris and Euphrates rivers has reduced by up to 40% since the 1970s, due in part to the actions of neighbouring countries, in particular Turkey, upstream.

Rising temperatures and reduced rainfall due to climate change are also negatively impacting Iraq’s water reserves. Evaporation from dams and reservoirs is estimated to lose the country up to 8 billion cubic metres of water every year.

A threat to peace and stability

Shortages have dried up previously fertile land, increasing poverty in agricultural areas. Shortages have also served to fuel conflict: communities faced with successive droughts and government inertia proved to be easy targets for ISIS recruiters, who lured farmers into joining them by offering money and food to feed their families. Economic hardship for those whose livelihoods relied upon river water has also driven rural to urban migration, putting significant strain on already over-populated towns and cities, exacerbating housing, job and electricity shortages, and widening the gap between haves and have-nots.

But scarcity isn’t the most crucial element of Iraq’s water crisis – contamination is. Decades of local government mismanagement, corrupt practices and a lack of regulation of dumping (it is estimated up to 70% of Iraq’s industrial waste is dumped directly into water) has left approximately three in every five citizens without a reliable source of potable water.

In 2018, 118,000 residents of Basra province were hospitalised with symptoms brought on by drinking contaminated water, which not only put a spotlight on the inadequacies of a crumbling healthcare system but sparked mass protests and a subsequent violent crackdown.

The water crisis is also undermining the stability of the country’s federal governance model, by occasionally sparking disputes between Baghdad and the Kurdistan Regional Government, as well as between governorates in the south.

The crisis is both a symptom and a cause of poor governance. Iraq is stuck in a cycle whereby government inaction causes shortages and contamination, which result in economic losses, reduced food supply, increased prices and widespread poor health. This in turn leads to increasing levels of poverty, higher demand on services and civil unrest, increasing the pressure on a weak, dysfunctional system of government.

What can be done?

The first priority should be modernising existing water-management infrastructure - a relic of a time when the problem was an excess rather than a shortage of water (the last time Iraq’s flood defences were required was 1968). Bureaucratic hurdles, widespread corruption and an endless cycle of other crises taking precedent prevent good initiatives from being implemented or scaled up.

Diversifying energy sources to improve provision is crucial. Baghdad has a sewage treatment plant that originally ran on its own electricity source, but this capacity was destroyed in 1991 and was never replaced. The city continues to suffer from dangerous levels of water pollution because the electricity supply from the grid is insufficient to power the plant. Solar energy has great potential in sun-drenched Iraq to bridge the gaping hole in energy provision, but successive governments have chosen to focus on fossil fuels rather than promoting investment to grow the renewables sector.

Heightened tension with upstream Turkey could turn water into another cause of regional conflict. But, if approached differently, collaboration between Iraq and its neighbour could foster regional harmony.

Turkey’s elevated geography and cooler climate mean its water reserves suffer 75% less evaporation than Iraq’s. Given that Turkey’s top energy priority is the diversification of its supply of imported hydrocarbons, a win-win deal could see Turkey exchange access to its water-management infrastructure for delivery of reduced cost energy supplies from Iraq.

German-French cooperation on coal and steel in the 1950s and the evolution of economic integration that followed might provide a model for how bilateral cooperation over one issue could result in cooperation with other regional players (in this case Iran and Syria) on a range of other issues. This kind of model would need to consider the future of energy, whereby oil and gas would be replaced by solar-power exports.

These solutions have been open to policymakers for years and yet they have taken little tangible action. While there are leaders and bureaucrats with the will to act, effective action is invariably blocked by a complex and opaque political system replete with vested interests in maintaining power and wealth via a weak state and limited services from central government.

Breaking the cycle

To break this cycle, Iraq needs a group of professional and able actors outside of government to work with willing elements of the state bureaucracy as a taskforce to pressure for action and accountability. Publishing the recommendations from a hitherto withheld report produced in the aftermath of Basra’s 2018 heath crisis would be a great start.

In time, this taskforce could champion the prioritisation of water on the national agenda, the implementation of infrastructure upgrades, and hold more productive conversations with neighbour states.

With such a high degree of state fragmentation and dysfunction in Iraq, looking to the central government to provide leadership will not yield results. Engagement with a coalition of non-state actors can begin to address the water crisis and also open a dialogue around new models of governance for other critical issues. This might even be a starting point for rewriting the tattered social contract in Iraq.

This piece is based on insights and discussion at a roundtable event, Conflict and the Water Crisis in Iraq, held at Chatham House on March 9 as part of the Iraq Initiative.




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Why is it So Hard for Iraq to Form A Government?

25 April 2020

Dr Renad Mansour

Senior Research Fellow, Middle East and North Africa Programme; Project Director, Iraq Initiative
Mustafa al-Kadhimi has emerged as the compromise prime minister designate, but his potential appointment is built on shaky foundations.

2020-04-25-Iraq-Security-COVID

A member of Iraqi security forces stands guard behind a yellow line after the government declared curfew due to coronavirus. Photo by Fariq Faraj Mahmood/Anadolu Agency via Getty Images.

On April 9, Iraqi President Barham Salih gathered the Shia, Kurdish and Sunni political blocs at the presidential palace to task head of intelligence Mustafa al-Kadhimi with forming a government.

Kadhimi is the third prime minister-designate assigned since Prime Minister Adil abd al-Mehdi resigned in November, in the wake of mass protests against government corruption and the country’s ethno-sectarian based political system.

Kadhimi’s two predecessors, Muhammad Tawfiq Allawi and Adnan al-Zurfi, both failed to form a government. This third attempt came as Iraq struggles with repeated crises since October 2019, when the government began responding with deadly force to large-scale mass protests, killing more than 600 and injuring tens of thousands.

In January, the assassination of Qasem Soleimani escalated tensions between the United States and Iran, with Iraq stuck in the middle and becoming the home for regular tit-for-tat attacks. The Islamic State — never completely defeated — took advantage of these crises and increased its attacks in disputed territories.

The outbreak of COVID-19 challenges the country’s fragile public health sector, while the decline in the price of oil will make it harder for leaders to pay the public salaries that keep the system (and patronage) moving.

What does the delay in forming a government amid multiple crises mean for the post-2003 Iraqi political system?

Iraq’s post-2003 political system is designed to withstand crisis. Over the years, political parties reflecting the country’s ethnic and sectarian divides have had a tacit understanding that crises represent a risk to their collective interests. These elite stakeholders have together weathered civil war, insurgency and multiple protests — despite deep conflicts with one another.

For instance, in September 2018 protesters attacked most major political party headquarters and the Iranian consulate in Basra, and authorities killed some 20 protesters.

Since the May election of that year, the fragmented Shia elite had been unable to even declare which side has the largest parliamentary bloc, let alone decide on a government.

But after the September crisis, the previously gridlocked parties swiftly came together to form an “understanding” that pushed through the impasse leading to the Mehdi government. In 2020, however, Iraq’s political parties were slower to come back together despite the multiple crises — far greater than 2018. The system is less able to swiftly fix itself, based primarily on the fragmentation of the elite — and their determination to prevent any challenge to their rule.

Why did the two prior attempts fail?

The two previous prime minister-designates each fell short for different reasons. When I met Allawi in February at the prime minister’s guesthouse in Baghdad, he was very clearly convinced that his mandate was to sideline the parties.

He hoped that simply choosing technocratic ministers outside the elite pact, with the support of Moqtada al-Sadr behind him, would garner support from protesters and the disillusioned public. He failed, however, because his cabinet had to go through parliament and the parties rejected what they saw a threat to the elite pact and the system.

Zurfi similarly failed after being directly appointed in March by Salih after the Shia parties failed to come up with a candidate. From the beginning, then, Zurfi faced challenges because parties were not in agreement. He attempted to directly confront his opposition, and spoke out against Iranian influence in Iraq. As a result, Zurfi was unable to even get to parliament with his proposed cabinet, as the Shia parties got back together to bring him down.

The failure of both strategies — Allawi attempting to work outside the elite party system and Zurfi trying to target certain parties — reveals tensions in Iraq’s political system. This fragmentation strains the parties’ ability to swiftly unite, and the system’s ability to withstand crises.

The endemic problems are a consequence of fragmentation, including the failure following the 2018 elections to declare governing parliamentary bloc. Moreover, after that election, newcomers into the political system (two-thirds of the MPs are serving their first term) are increasingly making their own demands and less willing to blindly toe party lines.

Can Kadhimi overcome the impasse?

Kadhimi’s appointment as prime minister-designate nonetheless is on shaky foundations. His appointment had previously faced a veto from Iran and its allied groups which make up the Fateh bloc. Kataeb Hezbollah, an armed group close to Iran and linked to the Popular Mobilization Units, issued a statement accusing Kadhimi with blood on his hands for the deaths of Soleimani and Abu Mahdi al-Muhandis.

Many Fateh bloc members had for months vetoed Kadhimi’s name due to this allegation. Immediately before Kadhimi addressed the nation for the first time, Iraqi state television broadcast a prerecorded statement by PMU (and Fateh) leader Qais al-Khazali, who had also previously accused Kadhimi of spying for the Americans and being complicit in the two killings.

Khazali, who commands the second-largest party within Fateh, accepted the party line to back Kadhimi but came out with his own conditions on television. However, the concerns about the COVID-19 crisis and the collapse of the price of oil finally brought all sides to compromise — a design of the political system.

Kadhimi has signalled he will play by the old rules with these stakeholders. Because of the magnitude of these simultaneous crises, Iraqi politics is moving back to the post-2003 norm. The ethno-sectarian based political system is geared to weather such existential crises more than it is to handling day-to-day governance. Despite the notion of “post-sectarianism” in Iraq, this system is based on ethno-sectarian political party compromise.

In his television address, Khazali, who had previously attempted to move away from sectarian language, explained that the process of selecting a prime minister is reserved to the Shia, who have the right as the majority, and not to Salih, a Kurd.

Over the years Kadhimi has expressed an admiration of the bravery of the protesters and of the importance of civil society. Many Iraqi civil society activists owe their lives to the work of the former intelligence chief. However, he has also been part of the same system that has violently suppressed protesters.

As the compromise prime minister-designate, he will find it difficult to transform his country as long as he plays by the rules of post-2003 Iraq — an irony not lost on the protesters who immediately rejected the candidacy of a man whom until recently many protesters had supported.

This article was originally published in The Washington Post




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The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation]

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.




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Russia and the New World Disorder

6 July 2015

A new book argues that Moscow’s approach to regional and global affairs reflects the tension between two very different worlds—the perceptual and the actual.

The Russian annexation of Crimea was one of the great strategic shocks of the past twenty-five years. For many in the West, Moscow’s actions in early 2014 marked the end of illusions about cooperation, and the return to geopolitical and ideological confrontation. Russia, for so long a peripheral presence, had become the central actor in a new global drama. In this groundbreaking book, renowned scholar Bobo Lo analyses the broader context of the crisis by examining the interplay between Russian foreign policy and an increasingly anarchic international environment. He argues that Moscow’s approach to regional and global affairs reflects the tension between two very different worlds—the perceptual and the actual.

The Kremlin highlights the decline of the West, a resurgent Russia, and the emergence of a new multipolar order. But this idealized view is contradicted by a world disorder that challenges core assumptions about the dominance of great powers and the utility of military might. Its lesson is that only those states that embrace change will prosper in the twenty-first century.

A Russia able to redefine itself as a modern power would exert a critical influence in many areas of international politics. But a Russia that rests on an outdated sense of entitlement may end up instead as one of the principal casualties of global transformation.

Praise for Russia and the New World Disorder

'Once again, Bobo Lo has written an illuminating book on Russia's foreign policy. He has achieved a real 'tour de force' in both conceptual and descriptive terms. With elegance and precision, Lo has explained why Russia, as a declining power, is still so important for international stability, crisis management, and global issues. A must-read for now, and certainly a classic book for the next decade.'
—Dr Thomas Gomart, Director of the French Institute of International Relations (IFRI), Paris

'Bobo Lo offers a trenchant analysis of the challenges and choices that confront Russia in today's rapidly changing global environment. In his compelling discussion of the Kremlin's Hobbesian view of the international system, he asks whether Russia is capable of jettisoning its imperial mindset and becoming a modern nation-state capable of interacting more effectively both with its neighbors and the wider world. His answer is sobering--and sometimes surprising.'
—Angela Stent, Director, Center for Eurasian, Russian and East European Studies (CERES), Georgetown University, and author of The Limits of Partnership: US-Russian Relations in the Twenty-First Century.

'Bobo Lo's new book is elegantly written and has a masterful grasp of the pressures and temptations that have acted on Putin in foreign and security policy. He puts us all in his debt.'
Robert Service, Fellow of the British Academy, and Emeritus Fellow, St Antony's College, University of Oxford

Editor's notes

Bobo Lo is an associate fellow with the Russia and Eurasia Programme at Chatham House, and an associate research fellow with the Russia and New Independent States Center at the French Institute of International Relations. He was previously director of the China and Russia programs at the Centre for European Reform, London; head of the Russia and Eurasia Programme at Chatham House; and deputy head of mission at the Australian Embassy in Moscow. He is the author of Axis of Convenience: Moscow, Beijing, and the New Geopolitics (Brookings/Chatham House, 2008).

Contacts

Press Office

+44 (0)20 7957 5739




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The resource curse has not been lifted

5 August 2015

20150804ResourceCurse2.jpg

Hoping to make a little money from Sudan's ocean of black gold, a woman sells tea to roughnecks at an oil rig near Bentiu, Sudan. Photo by Getty Images.

During a decade-long commodities boom, new or emerging producers of oil, gas or mineral resources registered some of the fastest rates of economic growth in the world. Development banks, governments giving foreign aid, extractives companies and major consultancies broadly agreed that ‘extractives-led growth’ is a viable path to socio-economic development for poor countries. 
               
Following over a year of decline in global commodities prices and as efforts to tackle climate change mount, a new paper re-examines the 'curse of natural resources'. It finds that a policy of extractives-led growth entails serious risks. As governments of countries as diverse as Afghanistan, Mauritania, Somalia, Liberia and Cuba prepare to follow an extractives-led growth path, both the advice being handed to them and the growth model itself require a fundamental rethink.

The Resource Curse Revisited argues that:

  • The steep decline in the oil price in the second half of 2014 demolished the main assumption of the extractives-led growth agenda. The assumption that prices of raw materials would continue to increase as global demand grew and well-established sources were exhausted has actually led several low- to middle-income producers such as Ghana into unmanageable debt. At the very least, the current price context  puts new producers at a serious disadvantage, as the focus on cost-cutting has made investors reluctant to accept the risks of developing projects in countries with little infrastructure or capacity to support them.

  • Good governance initiatives are not the antidote to the resource curse. There has often been a mismatch in terms of policy advice given (for example on transparency and revenue management) and the capacity of a country to implement it. Furthermore, basing economic growth on the extraction of below-ground resources will create strong pressures towards poor governance. In the absence of strong institutions, this path leads to the enrichment of minority elite groups, whose interest in capturing rents is likely to become a barrier to improving governance.

  • Both governments with extractives potential and those advising them give too little consideration to the size and nature of the resource base. If extractives-led growth is to be sustained, resource extraction must persist long enough for new economic sectors to emerge and generate revenues that can support government spending and import needs as income from extractives declines.
  • The extractives-led growth model, in its current form, is at odds with green growth strategies. The advice from international agencies and initiatives to countries with extractive resources offers no suggestions on how governments should manage the risk of stranded assets or how they can reconcile extractives-led growth with national sustainable-development goals.

The report concludes that the extractives-led growth agenda has tended to reinforce domestic, government and investor pressures to ‘develop fast’. However, this can threaten long-term opportunities for robust economic diversification. In many cases, there is a strong case for slowing development of extractives projects to allow time to develop the capacity of the government and the private sector to maximize the linkages with the rest of the economy.

Avoiding the resource curse needs not only good governance but also an economic policy that provides for the transition of an economy over time in accordance with its competitive advantages. This report recommends that countries considering extractives development, and their would-be advisors, take into account a wider set of issues at the outset including the likely value of the asset to the economy over time, the options for slow or indeed no development of extractives, and how the rest of the economy would lessen reliance on support from the extractives sector over time.

Editor's notes

Read the report The Resource Curse Revisited from the Energy, Environment and Resources Department, Chatham House.

For all enquiries, please contact the press office

Contacts

Press Office

+44 (0)20 7957 5739




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Chatham House appoints Tim Benton as Research Director for Energy, Environment and Resources

30 May 2019

Chatham House is pleased to announce that Professor Tim Benton has been appointed as research director of the Energy, Environment and Resources Department.

He brings substantial expertise on food systems and environmental change to the role and will focus on establishing new initiatives at the intersection of research and policymaking.

Tim was appointed as a distinguished visiting fellow of Chatham House in the Energy, Environment and Resources Department in 2016. He has since contributed to the institute in a number of ways, not least through leading the GCRF-AFRICAP project which aims to enhance policy making in Sub-Saharan Africa, through building climate-smart food systems.

Tim’s research focuses on food security and building food systems that are resilient and sustainable, working within the broader areas of ecology, natural resources and climate change impacts. He has published over 150 academic papers, most tackling the core themes of agriculture’s environmental impact and more generally how systems respond to environmental change. He is a lead author of the upcoming Intergovernmental Panel on Climate Change (IPCC) special report on climate change and land. He is also coordinating lead author on international risks for the UK’s Climate Change Risk Assessment, which draws on his broader interests in sustainable finance, trade and energy. He has advised other governments as well as global companies on related issues.

Tim joins Chatham House in his new capacity from the University of Leeds where he is dean of strategic research initiatives. Prior to this, from 2011 to 2016, Tim was the champion of the UK’s Global Food Security programme, a large multi-agency partnership of the UK’s public bodies involved in addressing challenges around food. He has also been research dean in the Faculty of Biological Sciences, and head of department, at Leeds.

Dr Robin Niblett, director of Chatham House, said: 'Tim’s wealth of experience will be especially valuable as we build up our interdisciplinary Chatham House research theme of promoting sustainable growth. We look forward to welcoming Tim to his new role in early July.'

Tim Benton said: 'I am honoured to be joining Chatham House as Research Director for Energy, Environment and Resources. Chatham House has a global reputation in these areas, on which we can build. Informed analysis, combined with effective action to transition towards sustainable economies, is needed now, more than ever.'

About the Energy, Environment and Resources Department

The Energy, Environment and Resources department at Chatham House seeks to advance the international debate on energy, environment and development policy and to influence and enable decision-makers – governments, NGOs and business – to take well-informed decisions that contribute to achieving sustainable development. Independent of any actor or ideology, we do this by carrying out innovative research on major policy challenges, bringing together diverse perspectives and constituencies and injecting new ideas into the international arena.

Tim Benton takes over the role from Rob Bailey who has joined Marsh & McLennan Insights as Director, Climate Resilience.




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Professor Robyn Alders, AO

Senior Consulting Fellow, Global Health Programme

Biography

Robyn Alders is a senior consulting fellow with the Chatham House Global Health programme focusing on policy opportunities to support sustainable livestock strategy implementation and sustainable food and nutrition security through a One Health lens.

Robyn is also an honorary professor with the Development Policy Centre within the Australian National University, an adjunct professor in the Department of Infectious Disease and Global Health, School of Veterinary Medicine, Tufts University, and chair of the Kyeema Foundation and Upper Lachlan Branch of the NSW Farmers’ Association. 

For more than 30 years, she has worked closely with family farmers in sub-Saharan Africa, South East Asia and Australia and as a veterinarian, researcher and colleague, with an emphasis on the development of sustainable infectious disease control in animals in rural areas in support of food and nutrition security and systems.

Areas of expertise

  • Domestic and global food and nutrition security/systems
  • Health security
  • One/Planetary Health
  • Gender equity
  • Science communication 

Past experience

2019 - presentHonorary professor, Development Policy Centre, Australian National University, Canberra, Australia
2012-18Professor of food and nutrition security, Faculty of Veterinary Science, University of Sydney, Australia

 




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South Africa Can Easily Afford National Health Insurance

9 December 2019

Robert Yates

Director, Global Health Programme; Executive Director, Centre for Universal Health
Countries with much lower per capita GDP have successfully implemented universal healthcare.

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Builders work on an outside yard at the Nelson Mandela Children's Hospital in Johannesburg in 2016. Photo: Getty Images.

At the United Nations general assembly in September, all countries, including South Africa, reaffirmed their commitment to achieving universal health coverage by 2030. This is achieved when everybody accesses the health services they need without suffering financial hardship.

As governments outlined their universal health coverage plans, it was noticeable that some had made much faster progress than others, with some middle-income countries outperforming wealthier nations. For example, whereas Thailand, Ecuador and Georgia (with national incomes similar to South Africa) are covering their entire populations, in the United States, 30 million people still lack health insurance and expensive health bills are the biggest cause of personal bankruptcy.

The key factor in financing universal health coverage is, therefore, not so much the level of financing but rather how the health sector is financed. You cannot cover everyone through private financing (including insurance) because the poor will be left behind. Instead, the state must step in to force wealthy and healthy members of society to subsidise services for the sick and the poor.

Switching to a predominantly publicly financed health system is, therefore, a prerequisite for achieving universal health coverage.

The National Health Insurance (NHI) Bill, recently presented to parliament, is President Cyril Ramaphosa’s strategy to make this essential transition. In essence, it proposes creating a health-financing system in which people pay contributions (mostly through taxes) according to their ability to pay and then receive health services according to their health needs.

Surprisingly, these reforms have been dubbed 'controversial' by some commentators in the South African media, even though this is the standard route to universal health coverage as exhibited by countries across Europe, Asia, Australasia, Canada and much of Latin America.

In criticising the NHI other stakeholders (often with a vested interest in preserving the status quo) have said that the government’s universal health coverage strategy is unaffordable because it will require higher levels of public financing for health.

Evidence from across the world shows that this is patently false. South Africa already spends more than 8% of its national income on its health sector, which is very high for its income level. Turkey, for example (a good health performer and slightly richer than South Africa), spends 4.3% of its GDP and Thailand (a global universal health coverage leader) spends only 3.7%. Thailand shows what can be accomplished, because it launched its celebrated universal health coverage reforms in 2002 when its GDP per capita was only $1 900 — less than a third of South Africa’s today.

In fact, Thailand’s prime minister famously ignored advice from the World Bank that it could not afford publicly financed, universal health coverage in the aftermath of the Asian financial crisis when it extended universal, tax-financed healthcare to the entire population. When these reforms proved a great success, a subsequent president of the World Bank, Dr Jim Kim, congratulated the Thai government for ignoring its previous advice.

Similarly the United Kingdom, Japan and Norway all launched successful universal health coverage reforms at times of great economic difficulty at the end of World War II. These should be salutary lessons for those saying that South Africa can’t afford the NHI. If anything, because universal health reforms generate economic growth (with returns 10 times the public investment), now is exactly the time to launch the NHI.

So there is enough overall funding in the South African health sector to take a giant step towards universal health coverage. The problem is that the current system is grossly inefficient and inequitable because more than half of these funds are spent through private insurance schemes that cover only 16% of the population — and often don’t cover even this population effectively.

Were the bulk of these resources to be channelled through an efficient public financing system, evidence from around the world shows that the health sector would achieve better health outcomes, at lower cost. Health and income inequalities would fall, too.

It’s true that in the long term, the government will have to increase public financing through reducing unfair subsidies to private health insurance and increasing taxes. But what the defenders of the current system don’t acknowledge is that, at the same time, private voluntary financing will fall, rapidly. Most families will no longer feel the need to purchase expensive private insurance when they benefit from the public system. It’s this fact that is generating so much opposition to the NHI from the private insurance lobby.

This is the situation with the National Health Service in the UK and health systems across Europe, where only a small minority choose to purchase additional private insurance. Among major economies, only the United States continues to exhibit high levels of private, voluntary financing.

As a consequence, it now spends an eye-watering 18% of its GDP on health and has some of the worst health indicators in the Organisation for Economic Co-operation and Development, including rising levels of maternal mortality. If South Africa doesn’t socialise health financing this is where its health system will end up — a long way from universal health coverage.

What countries celebrating their universal health coverage successes at the UN have shown is that it is cheaper to publicly finance health than leave it to the free market. This is because governments are more efficient and fairer purchasers of health services than individuals and employers. As Dr Gro Harlem Brundtland, the former director general of the World Health Organization, said in New York: 'If there is one lesson the world has learnt, it is that you can only reach UHC [universal health coverage] through public financing.'

This is a step South Africa must take — it can’t afford not to.

This article was originally published by the Mail & Guardian.




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Emerging Lessons From COVID-19

2 April 2020

Jim O'Neill

Chair, Chatham House
Exploring what lessons can be learned from the crisis to improve society and the functioning of our economic model going forward.

2020-04-02-COVID-Italy

A man with a protective mask by the Coliseum in Rome during the height of Italy's COVID-19 epidemic. Photo by ALBERTO PIZZOLI/AFP via Getty Images.

As tentative evidence emerges that Italy and Spain may have reached - or are close to - the peak of the curve, this could demonstrate that not only can Asian countries get to grips with COVID-19, but so can western democracies. And, if so, this offers a path for the rest of us.

The last few weeks does demonstrate there is a role for governments to intervene in society, whether it be health, finance or any walk of life, as they have had to implement social distancing. Some have been forced, and the interventions are almost definitely only temporary, but perhaps some others may be less so.

Governments of all kinds now realise there is a connection between our health system quality and our economic capability. On an index of global economic sustainability that I presided over creating when I was at Goldman Sachs, the top ten best performing countries on growth environment scores includes eight of the best performing ten countries - so far- in handling the crisis in terms of deaths relative to their population.

Health system quality

The top three on the index (last calculated in 2014) were Singapore, Hong Kong and South Korea, all of which are exemplary to the rest of us on how to deal with this mess. This suggests that once we are through this crisis, a number of larger populated countries - and their international advisors such as the IMF - might treat the quality of countries' health systems just as importantly as many of the other more standard indicators in assessing ability to deal with shocks.

Policymakers have also been given a rather stark warning about other looming health disasters, especially antimicrobial resistance, of which antibiotic resistance lies at the heart. An independent review I chaired recommended 29 interventions, requiring $42 bn worth of investment, essentially peanuts compared to the costs of no solution, and the current economic collapse from COVID-19. It would seem highly likely to me that policymakers are going to treat this more seriously now.

As a clear consequence of the - hopefully, temporary - global economic collapse, our environment suddenly seems to be cleaner and fresher and, in this regard, we have bought some time in the battle against climate change. Surely governments are going to be able to have a bigger influence on fossil fuel extractors and intense users as we emerge from this crisis?

For any industries requiring government support, the government can make it clear this is dependent on certain criteria. And surely the days of excessive use of share buy backs and extreme maximisation of profit at the expense of other goals, are over?

It seems to me an era of 'optimisation' of a number of business goals is likely to be the mantra, including profits but other things too such as national equality especially as it relates to income. Here in the UK, the government has offered its strongest fiscal support to the lower end of the income earning range group and, in a single swoop, has presided over its most dramatic step towards narrowing income inequality for a long time.

This comes on top of a period of strong initiatives to support higher levels of minimum earnings, meaning we will emerge later in 2020, into 2021, and beyond, with lower levels of income inequality.

The geographic issue of rural versus urban is also key. COVID-19 has spread more easily in more tightly packed cities such as London, New York and many others. More geographically remote places, by definition, are better protected. Perhaps now there will be some more thought given by policymakers to the quality and purpose of life outside our big metropolitan areas.

Lastly, will China emerge from this crisis by offering a mammoth genuine gesture to the rest of the world, and come up, with, unlike, in 2008, a fiscal stimulus to its own consumers, that is geared towards importing a lot of things from the rest of the world? Now that would be good way of bringing the world back together again.

This is a version of an article originally published in The Article




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The histone H4 basic patch regulates SAGA-mediated H2B deubiquitination and histone acetylation [DNA and Chromosomes]

Histone H2B monoubiquitylation (H2Bub1) has central functions in multiple DNA-templated processes, including gene transcription, DNA repair, and replication. H2Bub1 also is required for the trans-histone regulation of H3K4 and H3K79 methylation. Although previous studies have elucidated the basic mechanisms that establish and remove H2Bub1, we have only an incomplete understanding of how H2Bub1 is regulated. We report here that the histone H4 basic patch regulates H2Bub1. Yeast cells with arginine-to-alanine mutations in the H4 basic patch (H42RA) exhibited a significant loss of global H2Bub1. H42RA mutant yeast strains also displayed chemotoxin sensitivities similar to, but less severe than, strains containing a complete loss of H2Bub1. We found that the H4 basic patch regulates H2Bub1 levels independently of interactions with chromatin remodelers and separately from its regulation of H3K79 methylation. To measure H2B ubiquitylation and deubiquitination kinetics in vivo, we used a rapid and reversible optogenetic tool, the light-inducible nuclear exporter, to control the subcellular location of the H2Bub1 E3 ligase, Bre1. The ability of Bre1 to ubiquitylate H2B was unaffected in the H42RA mutant. In contrast, H2Bub1 deubiquitination by SAGA-associated Ubp8, but not by Ubp10, increased in the H42RA mutant. Consistent with a function for the H4 basic patch in regulating SAGA deubiquitinase activity, we also detected increased SAGA-mediated histone acetylation in H4 basic patch mutants. Our findings uncover that the H4 basic patch has a regulatory function in SAGA-mediated histone modifications.







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The Human Plasma Proteome: A Nonredundant List Developed by Combination of Four Separate Sources

N. Leigh Anderson
Apr 1, 2004; 3:311-326
Research




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Parallel Reaction Monitoring for High Resolution and High Mass Accuracy Quantitative, Targeted Proteomics

Amelia C. Peterson
Nov 1, 2012; 11:1475-1488
Technological Innovation and Resources




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High Resolution Clear Native Electrophoresis for In-gel Functional Assays and Fluorescence Studies of Membrane Protein Complexes

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research




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Quantitative, Multiplexed Assays for Low Abundance Proteins in Plasma by Targeted Mass Spectrometry and Stable Isotope Dilution

Hasmik Keshishian
Dec 1, 2007; 6:2212-2229
Research




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The Proteome of the Mouse Photoreceptor Sensory Cilium Complex

Qin Liu
Aug 1, 2007; 6:1299-1317
Research




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Time-resolved Mass Spectrometry of Tyrosine Phosphorylation Sites in the Epidermal Growth Factor Receptor Signaling Network Reveals Dynamic Modules

Yi Zhang
Sep 1, 2005; 4:1240-1250
Research




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Comparison of Label-free Methods for Quantifying Human Proteins by Shotgun Proteomics

William M. Old
Oct 1, 2005; 4:1487-1502
Research




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Absolute Quantification of Proteins by LCMSE: A Virtue of Parallel ms Acquisition

Jeffrey C. Silva
Jan 1, 2006; 5:144-156
Research




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Exponentially Modified Protein Abundance Index (emPAI) for Estimation of Absolute Protein Amount in Proteomics by the Number of Sequenced Peptides per Protein

Yasushi Ishihama
Sep 1, 2005; 4:1265-1272
Research




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Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents

Philip L. Ross
Dec 1, 2004; 3:1154-1169
Research




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Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics

Shao-En Ong
May 1, 2002; 1:376-386
Research




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The hibernating 100S complex is a target of ribosome-recycling factor and elongation factor G in Staphylococcus aureus [Protein Synthesis and Degradation]

The formation of translationally inactive 70S dimers (called 100S ribosomes) by hibernation-promoting factor is a widespread survival strategy among bacteria. Ribosome dimerization is thought to be reversible, with the dissociation of the 100S complexes enabling ribosome recycling for participation in new rounds of translation. The precise pathway of 100S ribosome recycling has been unclear. We previously found that the heat-shock GTPase HflX in the human pathogen Staphylococcus aureus is a minor disassembly factor. Cells lacking hflX do not accumulate 100S ribosomes unless they are subjected to heat exposure, suggesting the existence of an alternative pathway during nonstressed conditions. Here, we provide biochemical and genetic evidence that two essential translation factors, ribosome-recycling factor (RRF) and GTPase elongation factor G (EF-G), synergistically split 100S ribosomes in a GTP-dependent but tRNA translocation-independent manner. We found that although HflX and the RRF/EF-G pair are functionally interchangeable, HflX is expressed at low levels and is dispensable under normal growth conditions. The bacterial RRF/EF-G pair was previously known to target only the post-termination 70S complexes; our results reveal a new role in the reversal of ribosome hibernation that is intimately linked to bacterial pathogenesis, persister formation, stress responses, and ribosome integrity.




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12-LOX catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA2{gamma} knockout [Signal Transduction]

The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A2-mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA2γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses sn-1 specificity, with polyunsaturated fatty acids at the sn-2 position generating polyunsaturated sn-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-LOX) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-LOX oxidation products, 12(S)-HETE-LPC and 12(S)-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA2γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-LOX inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA2γ genetic ablation. Collectively, these results identify previously unknown iPLA2γ-initiated signaling pathways mediated by direct 12-LOX oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.




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G{alpha}q splice variants mediate phototransduction, rhodopsin synthesis, and retinal integrity in Drosophila [Signal Transduction]

Heterotrimeric G proteins mediate a variety of signaling processes by coupling G protein–coupled receptors to intracellular effector molecules. In Drosophila, the Gαq gene encodes several Gαq splice variants, with the Gαq1 isoform protein playing a major role in fly phototransduction. However, Gαq1 null mutant flies still exhibit a residual light response, indicating that other Gαq splice variants or additional Gq α subunits are involved in phototransduction. Here, we isolated a mutant fly with no detectable light responses, decreased rhodopsin (Rh) levels, and rapid retinal degeneration. Using electrophysiological and genetic studies, biochemical assays, immunoblotting, real-time RT-PCR, and EM analysis, we found that mutations in the Gαq gene disrupt light responses and demonstrate that the Gαq3 isoform protein is responsible for the residual light response in Gαq1 null mutants. Moreover, we report that Gαq3 mediates rhodopsin synthesis. Depletion of all Gαq splice variants led to rapid light-dependent retinal degeneration, due to the formation stable Rh1-arrestin 2 (Arr2) complexes. Our findings clarify essential roles of several different Gαq splice variants in phototransduction and retinal integrity in Drosophila and reveal that Gαq3 functions in rhodopsin synthesis.




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Biophysical characterization of SARAH domain-mediated multimerization of Hippo pathway complexes in Drosophila [Signal Transduction]

Hippo pathway signaling limits cell growth and proliferation and maintains the stem-cell niche. These cellular events result from the coordinated activity of a core kinase cassette that is regulated, in part, by interactions involving Hippo, Salvador, and dRassF. These interactions are mediated by a conserved coiled-coil domain, termed SARAH, in each of these proteins. SARAH domain–mediated homodimerization of Hippo kinase leads to autophosphorylation and activation. Paradoxically, SARAH domain–mediated heterodimerization between Hippo and Salvador enhances Hippo kinase activity in cells, whereas complex formation with dRassF inhibits it. To better understand the mechanism by which each complex distinctly modulates Hippo kinase and pathway activity, here we biophysically characterized the entire suite of SARAH domain–mediated complexes. We purified the three SARAH domains from Drosophila melanogaster and performed an unbiased pulldown assay to identify all possible interactions, revealing that isolated SARAH domains are sufficient to recapitulate the cellular assemblies and that Hippo is a universal binding partner. Additionally, we found that the Salvador SARAH domain homodimerizes and demonstrate that this interaction is conserved in Salvador's mammalian homolog. Using native MS, we show that each of these complexes is dimeric in solution. We also measured the stability of each SARAH domain complex, finding that despite similarities at both the sequence and structural levels, SARAH domain complexes differ in stability. The identity, stoichiometry, and stability of these interactions characterized here comprehensively reveal the nature of SARAH domain–mediated complex formation and provide mechanistic insights into how SARAH domain–mediated interactions influence Hippo pathway activity.




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DHHC7-mediated palmitoylation of the accessory protein barttin critically regulates the functions of ClC-K chloride channels [Cell Biology]

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.




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John Casson

Associate Fellow, Europe Programme

Biography

John Casson, CMG contributes to work on British power and foreign policy in the Brexit context, and on UK diplomacy and diplomatic leadership and formation.

He also contributes insights on middle east policy and multilateral diplomacy, drawing on his experience as British Ambassador in Cairo 2014-2018 and as the prime minister’s foreign policy lead in 10 Downing Street 2010-2014.

He spent 20 years as a civil servant in FCO, HMT and Downing Street.

Areas of expertise

  • EU and the UK’s European engagement
  • Egypt, and the Middle East
  • Transatlantic relations and multilateralism
  • International development and education
  • People-centred diplomacy: social media, faith and diplomacy, social entrepreneurship

Past experience

2014-18British Ambassador to Cairo
2010-14Private Secretary for Foreign Affairs, Prime Minister’s Office
1998-2018HM Diplomatic Service
1996-98Researcher, University of Cambridge (religion and politics in Africa)
1993-94Post-Graduate Diploma in Theology, University of Cambridge
1990-93BA in History, University of Cambridge 




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What Boris Johnson’s Big Win Means for Brexit and Scotland

13 December 2019

Thomas Raines

Director, Europe Programme

Jason Naselli

Senior Digital Editor
Thomas Raines tells Jason Naselli about the impact the large Conservative majority will have on the next phase of Brexit negotiations and Scotland’s place in the United Kingdom.

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Boris Johnson speaks after the Conservatives secured a majority in the UK general election. Photo: Getty Images.

What does the UK election result mean for Brexit and forthcoming trade negotiations with the EU?

The most important thing is that it means Brexit will definitely happen. Since the referendum, we’ve had three-and-a-half years of continued uncertainty where all outcomes were still possible. We now know that Brexit will become irreversible from 31 January.

That’s the biggest thing, because I think that will have a big psychological impact on politics, both in the UK and also on the EU side. The EU has been working with a partner that has been unsure about its direction, and perhaps some had still hoped that the process might still be reversed, but that direction is now completely clear.

Obviously the first order of business is to pass the withdrawal agreement, which should be pretty straightforward given the majority that the Conservatives have. That’s a formality now.

Then, the question becomes about the level of ambition for the next year. It is an exceptionally ambitious timetable to negotiate, ratify and implement a new relationship before the end of the transition period in December 2020.

What is achievable by the end of next year?

I think there are three possible outcomes here. One: that timetable doesn’t work and Boris Johnson follows through on his pledge to leave the transition period anyway, leading to a ‘no trade deal’ outcome.

Two: the negotiations are able to deliver something by the end of 2020, either because the depth and ambition of any agreement is relatively low level (what Michel Barnier has called a ‘vital minimum’)  and/or because they come up with some type of compromise on the process which is not called an extension, but something else: a type of temporary agreement or a new implementation period.

This is a situation where you might have a bare-bones agreement for the end of the transition period, but with an extended period of negotiation for different unresolved issues. The EU will probably insist upon level playing field guarantees and fishing access rights as a component of any such agreement.

Three: Boris Johnson breaks his manifesto pledge not to extend the transition. Now, he has stared down the barrel of leaving with no deal before and he made a political judgment that it was better to make significant compromises on his negotiating position than to follow through with ‘no deal’. I suspect he might make that same judgment again.

No option is ideal. The first is the most economically disruptive, the second means the EU will be in an even stronger position to dictate terms and the third means breaking a manifesto pledge.

How important is that end of transition deadline now? It was an important issue for the Brexit Party and hardliners in the European Research Group of Conservative MPs. But given the size of a majority, he may need to worry less about them. Is the transition deadline that important to people who voted Conservative, especially if he can show that he has taken the UK out of the EU by the end of January?

I think there may indeed be some political space for Johnson here, given the size of his majority and given that the first phase of Brexit will have been done, along with the debate about withdrawal.

There will be a lot of difficult, technical negotiations in all sorts of areas, some of which I think will become quite rancorous, but won’t necessarily become front page news in the way some of the first phase of negotiations has, not least because you won’t have the theatre of a hung parliament.

Hopefully, there will be more focus on the substance of the agreement, and the debate will be about the consequences of divergence versus staying more aligned with the EU, which is basically the central question now about the future relationship.

I still think for UK prime ministers to pick arbitrary dates, and then to make domestic political promises based around them, actually undermines the UK’s negotiating position. It would be in Britain’s interest to have more flexibility rather than a ticking clock.

Moving to the other big story from the night, the SNP won 48 of 59 seats in Scotland. How does the debate over Scotland’s future in the United Kingdom play out from here?

The SNP has really strengthened its position, more than many expected. This is now set up for a huge constitutional struggle over the future of the United Kingdom.

I think there is a key dilemma for Scottish independence supporters, which is that on the one hand Brexit greatly strengthens the political case for independence. The difference between the political preferences in Scotland and the rest of the UK, particularly in England, is a perfect demonstration of that.

At the same time, once the UK has left the EU, independence becomes much more difficult technically and economically. There will be many of the same difficulties that there have been in discussing Northern Ireland’s relationship with the Republic of Ireland. There will be a difficult debate over the currency. There are all sorts of challenges to creating a trade or regulatory border between England and Scotland. This is particularly true if there is a harder Brexit outcome, where Britain leaves the EU without a large amount of regulatory alignment.

On demands for a second independence referendum, I think in the first instance Boris Johnson will simply refuse to hold one. It’s probably not in his short-term interest to do anything else. Theresa May played it this way in 2017, repeatedly saying ‘now is not the time’.

In a similar way I think Johnson will just try to ride the pressure out, to the point where the SNP will need to face the challenges of advocating independence with the UK outside the EU. The next flashpoint will be the elections to the Scottish Parliament in 2021.

Ultimately, though, it will become a democratically unsustainable position if Scotland continues to vote for the SNP, and refusing to sanction a second independence referendum might only reinforce that sentiment.

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Biochemical and structural insights into how amino acids regulate pyruvate kinase muscle isoform 2 [Enzymology]

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.